Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.

OBJECTIVE: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN). METHODS: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?" RESULTS AND RECOMMENDATIONS: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.

A double-blind, randomized trial of duloxetine versus placebo in the management of chronic low back pain.

BACKGROUND: Duloxetine has demonstrated analgesic effect in chronic pain states. This study assesses the efficacy of duloxetine in chronic low back pain (CLBP). METHODS: Adult patients with non-radicular CLBP entered this 13-week, double-blind, randomized study comparing duloxetine 20, 60 or 120 mg once daily with placebo. The primary measure was comparison of duloxetine 60 mg with placebo on weekly mean 24-h average pain. Secondary measures included Roland-Morris Disability Questionnaire (RMDQ-24), Patient's Global Impressions of Improvement (PGI-I), Brief Pain Inventory (BPI), safety and tolerability. RESULTS: Four hundred four patients were enrolled, 267 completed. No significant differences existed between any dose of duloxetine and placebo on reduction in weekly mean 24-h average pain at end-point. Duloxetine 60 mg was superior to placebo from weeks 3-11 in relieving pain, but not at weeks 12-13. Duloxetine 60 mg demonstrated significant improvement on PGI-I, RMDQ-24, BPI-average pain and BPI-average interference. Significantly more patients taking duloxetine 120 mg (24.1%) discontinued because of adverse events, versus placebo (8.5%). CONCLUSIONS: Duloxetine was superior to placebo on the primary objective from weeks 3-11, but superiority was not maintained at end-point. Duloxetine was superior to placebo on many secondary measures, and was well-tolerated.

Efficient assessment of neuropathic pain drugs in patients with small fiber sensory neuropathies.

We sought to develop an enrichment crossover study design that would allow us to efficiently evaluate and compare promising candidate neuropathic pain drugs. We evaluated the efficacy of gabapentin or tramadol vs. active placebo (diphenhydramine) in subjects with biopsy-proven painful idiopathic small fiber neuropathy (SFN) who were self-reported gabapentin responders. Eligible subjects entered two single blind run-in phases. In the first phase (Period A), subjects were treated with single blinded gabapentin at their prestudy dose followed by a second run-in phase (Period B) in which they were treated with diphenhydramine active placebo. Subjects with >or=3 pain and a >or=30% increase in pain intensity in Period B compared to Period A were then randomized to a double-blind three period cross over trial of gabapentin at pre study dosage, tramadol 50mg QID and diphenhydramine 50mgqhs. Of the 59 subjects enrolled, 41 subjects were excluded: Twenty-three had an insufficient rise in pain intensity in Period B; eight had skin biopsies that did not confirm SFN. Eighteen subjects were randomized into the double-blind, crossover phase. There was a significant treatment effect of gabapentin vs. diphenhydramine (p=0.001) and tramadol vs. diphenhydramine (p=0.018) by the before-bed daily pain score averaged over the final 7 days of each treatment period. We conclude that gabapentin and tramadol were effective in the treatment of painful SFN and that this experimental enrichment paradigm is attractive to screen potential neuropathic pain compounds for efficacy in proof-of-concept studies.

A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain.

BACKGROUND: Nerve injury results in increases in spinal glutamate, which opens the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site must be occupied for the channel to open. GV196771 is a selective antagonist of the glycine-binding site of the NMDA ionophore. OBJECTIVE: To determine the efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of-concept study. METHODS: With informed consent, 63 subjects (31 placebo, 32 GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, or peripheral nerve injury), a visual analogue score averaging > or =30 mm during the screening period, and a well-defined primary area of mechanical allodynia were recruited for the study. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study design was utilized. Subjects came to the research center for a total of five visits over a 21-day period, which consisted of a 14-day treatment period followed by a 7-day washout period. Spontaneous and evoked pain scores, mechanical sensory testing, quantitative sensory testing, Short Form McGill Pain Questionnaire, patient global satisfaction, and safety assessments were made during the study. RESULTS: There was no significant effect of GV196771 on spontaneous or evoked pain, quantitative sensory testing, or patient global satisfaction. There was a significant effect of GV196771 on the area of dynamic and static allodynia on days 7 and 14. The overall incidence of adverse events during treatment was similar for GV196771 (56%) and placebo (71%). The incidence of drug-related adverse events during treatment was higher for placebo (42%) than GV196771 (28%). CONCLUSIONS: Although the glycine antagonists show anti-hyperalgesic action in animal models of neuropathic pain, GV196771 does not appear to be an effective treatment in subjects with chronic neuropathic pain. This may be due to insufficient penetration of GV196771 to central sites of action, differences between the human and animal glycine receptors, or differences between neuropathic pain in animal models and humans.

Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy.

Neuropathic pain, a form of chronic pain caused by injury to or disease of the peripheral or central nervous system, is a formidable therapeutic challenge to clinicians because it does not respond well to traditional pain therapies. Our knowledge about the pathogenesis of neuropathic pain has grown significantly over last 2 decades. Basic research with animal and human models of neuropathic pain has shown that a number of pathophysiological and biochemical changes take place in the nervous system as a result of an insult. This property of the nervous system to adapt morphologically and functionally to external stimuli is known as neuroplasticity and plays a crucial role in the onset and maintenance of pain symptoms. Many similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain models justify the rational for use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders. Carbamazepine, the first anticonvulsant studied in clinical trials, probably alleviates pain by decreasing conductance in Na+ channels and inhibiting ectopic discharges. Results from clinical trials have been positive in the treatment of trigeminal neuralgia, painful diabetic neuropathy and postherpetic neuralgia. The availability of newer anticonvulsants tested in higher quality clinical trials has marked a new era in the treatment of neuropathic pain. Gabapentin has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain, specifically for treatment of painful diabetic neuropathy and postherpetic neuralgia. Based on the positive results of these studies and its favourable adverse effect profile, gabapentin should be considered the first choice of therapy for neuropathic pain. Evidence for the efficacy of phenytoin as an antinociceptive agent is, at best, weak to modest. Lamotrigine has good potential to modulate and control neuropathic pain, as shown in 2 controlled clinical trials, although another randomised trial showed no effect. There is potential for phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine to have antihyperalgesic and antinociceptive activities based on result in animal models of neuropathic pain, but the efficacy of these drugs in the treatment of human neuropathic pain has not yet been fully determined in clinical trials. The role of anticonvulsant drugs in the treatment of neuropathic pain is evolving and has been clearly demonstrated with gabapentin and carbamazepine. Further advances in our understanding of the mechanisms underlying neuropathic pain syndromes and well-designed clinical trials should further the opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.

Anticonvulsants (antineuropathics) for neuropathic pain syndromes.

Our knowledge about the pathogenesis of neuropathic pain has grown significantly during last two decades. Basic research with animal models of neuropathic pain and human clinical trials with neuropathic pain have accumulated solid evidence that a number of pathophysiologic and biochemical changes take place in the nervous system at a peripheral or central level as a result of the insult or disease. Many similarities between the pathophysiologic phenomena observed in some epilepsy models and neuropathic pain models justify the rationale for the use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders. Carbamazepine (CBZ) was the first representative from this class of drugs to be studied in clinical trials. It has been used for the treatment of neuropathic pain syndromes, in particular, trigeminal neuralgia (TN), for the longest time of any of the drugs in this class. Results from clinical trials support the use of CBZ in the treatment of TN, painful diabetic neuropathy, and postherpetic neuralgia. The use of CBZ was not studied for complex regional pain syndrome, phantom limb pain, and other neuropathic conditions, however. Phenytoin was the first anticonvulsant to be used as an antinociceptive agent, but based on clinical trials, there is no evidence for its efficacy in relieving neuropathic pain. Newer anticonvulsants have marked a new era in the treatment of neuropathic pain, with clinical trials of higher quality standards. Gabapentin (GBP) has most clearly demonstrated an analgesic effect for the treatment of neuropathic pain, specifically for the treatment of painful diabetic neuropathy and postherpetic neuralgia. Gabapentin has a favorable side effects profile, and based on the results of these studies, it should be considered a first-line treatment for neuropathic pain. Gabapentin mechanisms of action are still not thoroughly defined, but GBP is effective in relieving indexes of allodynia and hyperalgesia in animal models. It still remains to be seen whether GBP is as effective in other painful disorders. One small clinical trial with lamotrigine demonstrated improved pain control in TN. Evidence in support of the efficacy of anticonvulsant drugs in the treatment of neuropathic pain continues to evolve, and benefits have been clearly demonstrated in the case of GBP and CBZ. More advances in our understanding of the mechanisms underlying neuropathic pain syndromes should further our opportunities to establish the role of anticonvulsants in the treatment of neuropathic pain.

Vulvar vestibulitis syndrome: a form of reflex sympathetic dystrophy?

OBJECTIVE: Our purpose was to determine whether vulvar vestibulitis syndrome is a form of reflex sympathetic dystrophy syndrome. MATERIALS AND METHODS: Between October 1, 1998, and February 16, 1999, 20 subjects attending a gynecology clinic at a tertiary care center received diagnoses of vulvar vestibulitis syndrome. A history was recorded, and a gynecological examination was performed for each, including a detailed description of the vulva, vaginal Gram's stain, vaginal culture, pH, and wet preparation of any discharge. Vulvar examination included assessing each subject's response to touch, pressure, pinprick, vibration, and cold. Subjects completed the short form of the McGill Pain Questionnaire. RESULTS: Twenty subjects with vulvar vestibulitis syndrome (average age, 30.6 years; range, 20-71 years) had pain present an average of 4 years and 8 months (range, 6 months-33 years). Pain occurred with entry dyspareunia, tampon insertion, or touching of the vestibule. Vulvar vestibular erythema was present in 13 subjects. None of the 20 subjects felt pain to light touch on the vulvar vestibule. Light pressure produced allodynia in all 20. Nine subjects had hyperalgesia to pinprick; five subjects had allodynia in response to vibration; and three subjects experienced allodynia to cold. Summation and aftersensation to test modalities were uncommon. CONCLUSION: Though both vulvar vestibulitis and reflex sympathetic dystrophy seem to be neuropathic pain syndromes, they do not share enough physical characteristics to be considered the same pathological processes.

Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive?

This is a multisite study examining the internal validity and comprehensiveness of the International Association for the Study of Pain (IASP) diagnostic criteria for Complex Regional Pain Syndrome (CRPS). A standardized sign/symptom checklist was used in patient evaluations to obtain data on CRPS-related signs and symptoms in a series of 123 patients meeting IASP criteria for CRPS. Principal components factor analysis (PCA) was used to detect statistical groupings of signs/symptoms (factors). CRPS signs and symptoms grouped together statistically in a manner somewhat different than in current IASP/CRPS criteria. As in current criteria, a separate pain/sensation criterion was supported. However, unlike in current criteria, PCA indicated that vasomotor symptoms form a factor distinct from a sudomotor/edema factor. Changes in range of motion, motor dysfunction, and trophic changes, which are not included in the IASP criteria, formed a distinct fourth factor. Scores on the pain/sensation factor correlated positively with pain duration (P<0. 001), but there was a negative correlation between the sudomotor/edema factor scores and pain duration (P<0.05). The motor/trophic factor predicted positive responses to sympathetic block (P<0.05). These results suggest that the internal validity of the IASP/CRPS criteria could be improved by separating vasomotor signs/symptoms (e.g. temperature and skin color asymmetry) from those reflecting sudomotor dysfunction (e.g. sweating changes) and edema. Results also indicate motor and trophic changes may be an important and distinct component of CRPS which is not currently incorporated in the IASP criteria. An experimental revision of CRPS diagnostic criteria for research purposes is proposed. Implications for diagnostic sensitivity and specificity are discussed.

Gabapentin monotherapy for the symptomatic treatment of painful neuropathy: a multicenter, double-blind, placebo-controlled trial in patients with diabetes mellitus.

Pain is the most disturbing symptom of diabetic neuropathy. Traditionally this type of pain was treated with tricyclic antidepressants which frequently have many side effects. In the study reported here, gabapentin was administered in escalating doses up to 3600 mg per day to eligible patients with moderate to severe diabetic neuropathy pain in a double blind placebo controlled fashion. Gabapentin provided superior and significant pain relief over placebo. In addition, patients taking gabapentin had improvement of sleep scores and a number of items on mood and quality of life questionnaires. Gabapentin was tolerated well with mild and tolerable side effects.

External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain.

Recent work in our research consortium has raised internal validity concerns regarding the current IASP criteria for Complex Regional Pain Syndrome (CRPS), suggesting problems with inadequate sensitivity and specificity. The current study explored the external validity of these IASP criteria for CRPS. A standardized evaluation of signs and symptoms of CRPS was conducted by study physicians in 117 patients meeting IASP criteria for CRPS, and 43 patients experiencing neuropathic pain with established non-CRPS etiology (e.g. diabetic neuropathy, post-herpetic neuralgia). Multiple discriminant function analyses were used to test the ability of the IASP diagnostic criteria and decision rules, as well as proposed research modifications of these criteria, to discriminate between CRPS patients and those experiencing non-CRPS neuropathic pain. Current IASP criteria and decision rules (e.g. signs or symptoms of edema, or color changes or sweating changes satisfy criterion 3) discriminated significantly between groups (P < 0.001). However, although sensitivity was quite high (0.98), specificity was poor (0.36), and a positive diagnosis of CRPS was likely to be correct in as few as 40% of cases. Empirically-based research modifications to the criteria, which are more comprehensive and require presence of signs and symptoms, were also tested. These modified criteria were also able to discriminate significantly, between the CRPS and non-CRPS groups (P < 0.001). A decision rule, requiring at least two sign categories and four symptom categories to be positive optimized diagnostic efficiency, with a diagnosis of CRPS likely to be accurate in up to 84% of cases, and a diagnosis of non-CRPS neuropathic pain likely to be accurate in up to 88% of cases. These results indicate that the current IASP criteria for CRPS have inadequate specificity and are likely to lead to overdiagnosis. Proposed modifications to these criteria substantially improve their external validity and merit further evaluation.

Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial.

CONTEXT: Pain is the most disturbing symptom of diabetic peripheral neuropathy. As many as 45% of patients with diabetes mellitus develop peripheral neuropathies. OBJECTIVE: To evaluate the effect of gabapentin monotherapy on pain associated with diabetic peripheral neuropathy. DESIGN: Randomized, double-blind, placebo-controlled, 8-week trial conducted between July 1996 and March 1997. SETTING: Outpatient clinics at 20 sites. PATIENTS: The 165 patients enrolled had a 1- to 5-year history of pain attributed to diabetic neuropathy and a minimum 40-mm pain score on the Short-Form McGill Pain Questionnaire visual analogue scale. INTERVENTION: Gabapentin (titrated from 900 to 3600 mg/d or maximum tolerated dosage) or placebo. MAIN OUTCOME MEASURES: The primary efficacy measure was daily pain severity as measured on an 11-point Likert scale (0, no pain; 10, worst possible pain). Secondary measures included sleep interference scores, the Short-Form McGill Pain Questionnaire scores, Patient Global Impression of Change and Clinical Global Impression of Change, the Short Form-36 Quality of Life Questionnaire scores, and the Profile of Mood States results. RESULTS: Eighty-four patients received gabapentin and 70 (83%) completed the study; 81 received placebo and 65 (80%) completed the study. By intent-to-treat analysis, gabapentin-treated patients' mean daily pain score at the study end point (baseline, 6.4; end point, 3.9; n = 82) was significantly lower (P<.001) compared with the placebo-treated patients' end-point score (baseline, 6.5; end point, 5.1; n = 80). All secondary outcome measures of pain were significantly better in the gabapentin group than in the placebo group. Additional statistically significant differences favoring gabapentin treatment were observed in measures of quality of life (Short Form-36 Quality of Life Questionnaire and Profile of Mood States). Adverse events experienced significantly more frequently in the gabapentin group were dizziness (20 [24%] in the gabapentin group vs 4 [4.9%] in the control group; P<.001) and somnolence (19 [23%] in the gabapentin group vs 5 [6%] in the control group; P = .003). Confusion was also more frequent in the gabapentin group (7 [8%] vs 1 [1.2%]; P = .06). CONCLUSION: Gabapentin monotherapy appears to be efficacious for the treatment of pain and sleep interference associated with diabetic peripheral neuropathy and exhibits positive effects on mood and quality of life.

Pain assessment and evaluation of patients who have neuropathic pain.

Pain assessment and physical examination are the first crucial steps in diagnosis of neuropathic pain disorders because these are still solely diagnosed on clinical grounds. The physical examination should be conducted in such a way that all of the positive sensory phenomena, such as allodynia, hyperalgesia, hyperpathia, summation, and after-sensation are elicited. Other physical examination findings should corroborate the diagnostic impression of neuropathic pain. Specific pain diagnosis should then lead to more specific therapy.

Traumatic neuralgias: complex regional pain syndromes (reflex sympathetic dystrophy and causalgia): clinical characteristics, pathophysiological mechanisms and therapy.

Complex regional pain syndromes (CPRS) may develop as a disproportionate consequence of a trauma affecting the limbs without (CRPS I, reflex sympathetic dystrophy) or with (CRPS II, causalgia) obvious nerve lesions. The clinical picture of CRPS consists of asymmetrical distal extremity pain, swelling, and autonomic (sympathetic) and motor symptoms. Changes in the peripheral and central somatosensory, autonomic and motor processing, and a pathologic interaction of sympathetic and afferent systems are discussed as underlying pathophysiologic mechanisms. Therapeutic strategies include pharmacologic pain relief, sympatholytic interventions, and rehabilitation.

Effects of oral morphine on cold pressor tolerance time and neuropsychological performance.

We investigated the analgesic effects of escalating doses (0.214, 0.286, 0.357, and 0.429 mg/kg) of oral morphine on tolerance to painful cold pressor in a double-blind, active placebo-controlled (diphenhydramine) study in 45 normal volunteers. The highest dose of morphine administered is equivalent to the starting dose recommended by the Agency for Health Care Policy and Research for the management of cancer pain and acute postoperative pain. We assessed analgesia in terms of cold pressor tolerance time and self-reported ratings of pain intensity and unpleasantness. Subjects receiving the highest dose of oral morphine showed significantly higher tolerance time than subjects receiving diphenhydramine. Neither morphine or diphenhydramine significantly reduced ratings of pain intensity and unpleasantness. Neuropsychological testing revealed that the two highest doses of morphine impaired the episodic retrieval of a word list, but the same doses did not affect motor, perceptual, or attentional tasks.

The effect of continuous morphine analgesia on chronic thermal hyperalgesia due to sciatic constriction injury in rats.

We employed hindfoot withdrawal latencies to radiant heat to assess the analgesic effect of prolonged morphine infusion on thermal hyperalgesia induced by chronic constriction injury (CCI) of the rat sciatic nerve. All CCI rats developed thermal hyperalgesia while sham-operated animals did not. Continuous systemic infusion of morphine dose-dependently reversed the thermal hyperalgesia in the CCI rats. In contrast, thermal hyperalgesia persisted in saline-treated CCI rats. Tolerance to morphine's analgesic effect did not develop over a period of seven days of morphine infusion, which is considered long-term for animal models. These data suggest that morphine acts rapidly and effectively to reduce behavioral signs of hyperalgesia in rats with sciatic CCI, without the concomitant development of tolerance. Scheduled administration of morphine might be an appropriate treatment regimen for relief of neuropathic pain, and the infrequent use of opioids in equivalent human clinical pain syndromes due to fear of opioid unresponsiveness and tolerance might need to be re-evaluated.

Local anesthetics as adjuvant analgesics.

Local anesthetics administered to block nerve conduction for surgical anesthesia and to provide analgesia in management of acute pain have become a standard of anesthesiology practice. These drugs have had an important role in the multimodality management of chronic pain as well, and this role is expanding since the revival of systemic administration. Local anesthetics are analgesics, albeit not in the traditional clinical and pharmacologic sense. Evidence suggests that intravenous administration is an effective treatment in chronic neuropathic pain syndromes. There is also evidence that intravenous local anesthetics can relieve acute pain. Furthermore, the novel idea that acute procedural and postprocedural pain control with local anesthetics could prevent the development of chronic pain syndromes, including chronic neuropathic pain syndromes, adds another important potential dimension to the role of local anesthetics in pain management.